Clinical evaluation of targeted cancer therapy is currently hampered by the difficulty in matching a new molecularly targeted agent to the appropriate molecular-defined patient. The solution requires the use of molecularly-based biomarkers to guide patient selection, optimize drug dosage and assess response to treatment. This project will use two well-annotated, genetically-defined mouse models of human prostate cancer to discover biomarkers that define disease progression, the initiating oncogenic lesion and response to therapy. The molecular profiles of these mouse models closely resemble human prostate cancers, giving us confidence in their utility for discovery of human tumor biomarkers. In addition, we have already demonstrated that dominant molecular signatures of disease stage and the initiating molecular lesion are easily detected in both models. Aim 1 of this project will use existing mRNA and proteomics datasets to define the optimal mRNA signatures from tumor tissue and protein signatures from serum to determine disease stage, molecular lesion and response to therapy (in collaboration with the Hood lab). We will then develop nanodevices for measuring these mRNA signatures from small numbers of cells (in collaboration with Fluidigm) and Si-based nanodevices for measuring serum protein signatures (in collaboration with the Heath lab). We will then evaluate and optimize the performance of these nanodevices in mice (Aim 2) and in patients (Aim 3) treated with two different kinase inhibitors as well as using more conventional blood proteomics analyses for these studies (in collaboration with Hood lab). Success in the project will provide proof-of-concept for detailed molecular evaluation of cancer patients before and during therapy using highly accurate, cost-effective and minimally invasive technologies.